Stem cell therapy has been proposed for treating a variety of disease states or medical conditions, such as myocardial infarction (Zhao et al., 2008, J Appl Physiol 104:1793-800), spinal cord injury (Liu et al., 2011, Neurol Res 33:686-93), ALS (Lepore & Maragakis, 2011, Methods Mol Biol 793:479-93), muscular dystrophy (Expert Opin Biol Ther 11:157-76), Parkinson's disease (Azizi et al., 1998, Proc Natl Acad Sci USA 95:3908-13), Huntington's disease (Dinsmore et al., 1996, Cell Transplant 5:131-43), type 1 diabetes (Assady et al., 2001, Diabetes 50:1691-97), graft-versus-host disease (GVHD) (Taupin, 2006, Curr Opin Investig Drugs 7:473-81), Crohn's disease (Taupin, 2006, Curr Opin Investig Drugs 7:473-81) chronic obstructive pulmonary disease (Ribeiro-Paes et al., 2011, Int J Chron Obstruct Pulmon Dis 6:63-71), macular degeneration (Du et al., 2011, Semin Ophthalmol 26:216-24), osteoarthritis (Pak, 2011, J Med Case Reports 5:296), autoimmune disease (Zeher et al., 2011, Expert Opin Biol Ther 11:1193-201) and organ failure (Russo & Parola, 2011, Cytotherapy 13:135-44).
Administration of stem cells for treating such diseases typically involves delivery by injection at or near a target site (see, e.g., Boudoulas and Hatzopoulos, 2009, Dis Model Mech 2:344-58; Azizi et al., 1998, Proc Natl Acad Sci USA 95:3908-13). However, injection or infusion of stem cells may not result in significant levels of retention and engraftment at the target site (Gundlach et al. 2011, Bioconj Chem 22:1706-14). Direct injection may also affect the frequency of teratoma formation, an undesirable side effect of stem cell administration (see, e.g., Gutierrez-Aranda et al., 2010, Stem Cells 28:1568-70). A need exists for more effective delivery of stem cells to targeted locations, with better retention and engraftment in the target tissue or organ.
One approach to improved stem cell delivery involves use of bispecific antibodies with a first binding site for a stem cell antigen and a second binding site for a target tissue antigen (Lum et al., 2004, Blood Cells Mol Dis 32:82-7; Lum et al., 2006, Exp Hematol 34:1-6; Lee et al., 2007, Stem Cells 25:712-17; Zhao et al., 2008, J Appl Physiol 104:1793-800; Gundlach et al. 2011, Bioconj Chem 22:1706-14). Such bispecific antibodies would serve to localize the stem cell to the tissue targeted for therapy and improve retention at the target site to promote integration into the tissue. Gundlach et al. (2011) used anti-myosin light chain 1 (MLC1)× anti-CD90 bispecific antibodies to target bone marrow-derived multipotent stromal cells (BMMSC) to damaged tissue in infarcted myocardium. The bispecific antibody was reported to promote BMMSC binding to immobilized MLC1 in vitro. However, no studies were performed to demonstrate localization, retention and integration in vivo. Lee et al. (2007) used a bispecific anti-MLC× anti-CD45 antibody to target hematopoietic stem cells (HSCs) to ischemic myocardium in rats. In the presence of bispecific antibody the CD34+ HSCs were localized to the infarcted region of the rat heart (Id.). Use of bispecific antibody was reported to improve delivery to stem cells to injured myocardium, compared to the absence of antibody, and was correlated with improved myocardial function 5 weeks after infarction (Id.). Zhao et al. (2008) targeted HSCs to ischemic myocardium with an anti-CD45× anti-MLC bispecific antibody in mice and reported improved ventricular function to control animals who received no HSCs. Because of the absence of a control administration of HSCs in the absence of antibody, it was not possible to attribute the improved cardiac function to the bispecific antibody.
Existing technologies for the production of bispecific antibodies suffer a number of limitations. For agents generated by recombinant engineering, such limitations may include high manufacturing cost, low expression yields, instability in serum, instability in solution resulting in formation of aggregates or dissociated subunits, undefined batch composition due to the presence of multiple product forms, contaminating side-products, reduced functional activities or binding affinity/avidity attributed to steric factors or altered conformations, etc. For agents generated by various methods of chemical cross-linking, high manufacturing cost and heterogeneity of the purified product are two major limitations. A need exists in the art for improved bispecific antibody complexes for targeted stem cell delivery.